The concepts of stunned and hibernating myocardium were described and received considerable
attention in the 1980s. These phenomena, related to myocardial ischemia (Figure 1),
occur far more frequently than when they were initially described. This article defines
these conditions, summarizes what has been learned about them since their original
descriptions, and shows current importance of their understanding.
Figure 1
The schematic documents 3 possible outcomes of myocardial ischemia. On the left is
the situation of severe and prolonged myocardial ischemia. The myocardial cells die
resulting in a myocardial infarction, are replaced by scar tissue, and do not recover
contractile function. In the middle is the scenario in which the duration and severity
of myocardial ischemia are not long enough or severe enough to kill cells. When the
ischemia is relieved by reperfusion, the myocardium is viable but stunned, exhibiting
transient post‐ischemic contractile and biochemical dysfunction. Recovery of the stunned
myocardium eventually occurs but may take days to weeks. The third scenario of ischemia
is shown on the right. Chronic low blood flow results in metabolic adaptations allowing
the cardiomyocytes to survive, but these cells do not contract at rest and exhibit
typical morphology of dedifferentiation. Once revascularized, these hibernating myocardial
cells eventually recover function, but this may require weeks to months as the contractile
apparatus replenishes. In addition, another theory of hibernating myocardium is shown
in which repetitive episodes of ischemic, stunned myocardium occur when coronary artery
reserve cannot meet an increase in myocardial oxygen demand. These repetitive episodes
of stunning lead to a chronic reduction in contractile function and metabolic adaptation
to allow for cell survival.
Stunned Myocardium
Background
In 1982, Braunwald and Kloner1 described stunning as “prolonged, post‐ischemic ventricular
dysfunction that occurs after brief periods of nonlethal ischemia.” They proposed
that myocardial stunning may be thought of as a “hit” (an episode of severe ischemia),
“run” (the relief of the ischemia before significant irreversible injury occurs),
and “stun” (a relatively long period of post‐ischemic contractile dysfunction). The
cardiac muscle eventually recovers fully, but during the phase of impaired function,
it may require inotropic support. Stunned myocardium is also associated with prolonged
biochemical abnormalities that may take days to resolve following initial resolution
of ischemia. Delayed recovery following ischemia was first described in experimental
animal studies in the 1970s and 1980s. Dogs were exposed to occlusions of a major
coronary artery for up to 15 minutes, followed by reperfusion. This duration of ischemia
causes largely “reversible” injury because it is not long enough to lead to detectable
myocardial necrosis. (As described below, with more sensitive methods for detecting
necrosis, evidence of apoptotic cell death has been identified.) Regional ventricular
wall motion was measured with techniques such as ultrasonic crystals implanted in
the walls of the ventricle.2, 3 The myocardium perfused by the occluded artery became
akinetic or dyskinetic during ischemia. When blood flow was restored by removing the
coronary artery clamp or ligation, contractile function remained depressed initially
but then gradually recovered over the course of a few days. Cardiac ATP levels also
demonstrated a biochemical stunning as levels were depressed within 15 minutes of
coronary artery occlusion and gradually recovered toward normal by 72 hours of reperfusion.4
Histologic analysis revealed viable myocardial cells at 72 hours after reperfusion.
Numerous laboratories demonstrated the phenomenon of stunned myocardium.5, 6 Whereas
stunning was initially associated with brief periods of ischemia not associated with
histologic evidence of cell death, other studies showed that this phenomenon occurred
in models of myocardial infarction (MI), within the salvaged outer wall of the ventricle.
In this case, the recovery of function following reperfusion of an experimental MI
was even more prolonged, requiring days to weeks.7 Our research group showed that
the contractile function of stunned myocardium could be supported with inotropes in
the reperfused myocardial infarct models, without extending infarct size, as long
as reperfusion had occurred and was complete.8, 9
There has been considerable interest in the mechanism(s) responsible for stunned myocardium.
The 2 leading hypotheses are oxygen radical damage that occurs in the first few minutes
of reperfusion and altered calcium flux with calcium overload that then desensitizes
the myofilaments.10, 11 Zweier et al12 used spin trap techniques to show that there
was a sizable burst of oxygen‐centered free radicals that occurs within the first
10 seconds of reperfusion. Oxygen free radicals are known to disrupt biologic systems
including membranes and contractile apparatus. In an experimental model of 15 minutes
of occlusion and 3 hours of reperfusion, Przyklenk et al13 showed that treatment with
the oxygen free radical scavengers superoxide dismutase and catalase improved the
contractility of stunned myocardium. Others also showed that oxygen radical scavengers
were effective.10 The calcium blockers nifedipine14 and verapamil15 were shown to
improve the recovery of stunned myocardium; the latter also partially preserved ATP
levels. The calcium overload may result in decreased responsiveness of the myofilaments
to calcium. More recently, it has been postulated that sarcoplasmic reticulum dysfunction
may result in excitation‐contraction uncoupling as another component of the mechanism
for stunning.16 In addition, a 2006 study showed that pretreatment of rabbits with
ranolazine, an inhibitor of the late sodium channel current, also reduced stunning
without any effect on hemodynamics, suggesting that the late sodium current may also
play a role.17
Initial clinical evidence for stunned myocardium was substantiated by several observations:
(1) the gradual return of regional function following thrombolytic therapy for acute
MI, (2) prolonged left ventricular (LV) regional wall motion abnormalities in patients
with unstable angina, (3) prolonged diastolic dysfunction following brief angioplasty
balloon inflations and deflations, (4) persistent LV regional wall motion abnormalities
following exercise‐induced ischemia, and (5) prolonged but reversible LV dysfunction
following cardiac surgery1, 18, 19, 20 (Table 1). Stunned myocardium continues to
be diagnosed in several different clinical scenarios.16
Table 1
Clinical Evidence of Stunned Myocardium
Gradual return of regional function following thrombolytic therapy or percutaneous
coronary intervention for the treatment of acute myocardial infarction
Prolonged regional wall motion abnormalities in patients with unstable angina pectoris
Persistent left ventricular regional wall motion abnormalities following exercise‐induced
ischemia
Prolonged but reversible left ventricular dysfunction following cardiac surgery
Relatively prolonged abnormality in systolic and diastolic function following coronary
artery angioplasty balloon inflation and deflation
Conditions that may be caused by stunned myocardium: stress (Takotsubo) cardiomyopathy,
“neurogenic stunned myocardium,” and dialysis‐related ventricular dysfunction
Is Stunning Relevant in the PCI Era?
Whereas initial descriptions supporting the concept of stunned myocardium in humans
occurring after reperfusion for acute MI came from the thrombolytic therapy literature,21
is there evidence for myocardial stunning in the percutaneous coronary intervention
(PCI) era? Wdowiak‐Okrojek et al22 recently evaluated 97 patients with acute MI who
were treated successfully with PCI and followed their cardiac function with serial
2‐dimensional echocardiographic speckle tracking following revascularization. They
observed the greatest improvement in regional systolic function occurring between
day 1 and 2 of reperfusion. On days 3 to 180 there was further improvement in systolic
function but not as marked as during the first 2 days. Recovery of diastolic function
took longer with the most significant improvement occurring very gradually over the
first 7 days of reperfusion. This study showed that systolic and diastolic stunning
is noted in 2019, despite the most up‐to‐date reperfusion strategies. In another study
of PCI‐treated acute MIs, gated single‐photon emission computed tomography myocardial
perfusion imaging was performed before hospital discharge and 6 months after hospital
discharge in 120 patients. LV ejection fraction (LVEF) just before discharge was 47%
and late EF was 51%; 54 patients showed an increase in EF of >5 units. Recovery of
LVEF correlated to the amount of salvaged myocardium.23 Other studies have shown that
myocardial stunning occurs following PCI for ST‐segment–elevation MI.24
Recent reports have confirmed that stunned myocardium occurs after even brief inflations
of an angioplasty balloon in the coronary artery of patients undergoing elective PCI.
McCormick et al25 studied 20 patients with preserved LV function and single vessel
coronary artery disease (CAD) who were undergoing elective PCI. They placed a conductance
catheter into the LV cavity and measured hemodynamics and pressure‐volume loops at
baseline, during balloon inflation (coronary artery occlusion) and at 30 minutes of
recovery (after balloon deflation). LV dysfunction was observed both during balloon
inflation as well as at 30 minutes after deflation. At 30 minutes of reperfusion,
cardiac output, EF, dP/dT max remained reduced and Tau remained elevated, consistent
with stunning. Of note, pretreatment with glucagon‐like peptide‐1 protected the patients
against ischemic LV dysfunction and stunning.
Although experimental studies showed that oxygen free radical scavengers, calcium
blockers, and late sodium current inhibitors could improve the function of stunned
myocardium, a recent clinical study suggested that the heart rate slowing drug, ivabradine,
can prevent stunned myocardium associated with exercise inducible ischemia in coronary
artery patients. In 15 patients with CAD, echocardiography was used to assess stunning.
LV longitudinal strain was impaired during exercise at peak stress and for several
minutes of recovery. After 2 weeks of ivabradine therapy, repeated stress echocardiograms
showed that the drug prevented the impairment of LV function during recovery.26
Conditions That May Be Caused By Stunned Myocardium
Several recent reports have suggested that certain conditions whose exact cause remains
to be determined, may be a manifestation of stunned myocardium. While the original
description of stunned myocardium describes prolonged return of function after relief
of a discrete episode of ischemia, these conditions may, but have not been unequivocally
shown to, reflect ischemia followed by relief of ischemia. Therefore, it is safer
at this point to state that these conditions may be, rather than definitively are,
manifestations of stunning.
Stress cardiomyopathy or Takotsubo cardiomyopathy (Table 2) is one such example. This
entity is characterized by chest pain, dyspnea, signs of ischemia on ECG (including
transient ST‐segment–elevation and T‐wave inversion), elevated cardiac enzymes, transient
LV apical ballooning with sparing of the basal portion of the left ventricle, and
exclusion of significant organic stenosis in the coronary arteries. The circumferential
nature of the transient LV wall motion abnormalities extend beyond the distribution
of a single epicardial coronary artery, suggesting that, unlike most acute MIs, an
occlusion in a single coronary artery cannot explain the extent of the wall motion
abnormality.27 Takotsubo cardiomyopathy often occurs in postmenopausal women and is
preceded by emotional stress. This disease may account for up to 1% to 2% of all patients
hospitalized with the initial diagnosis of acute ST‐segment–elevation MI. Because
the LV dysfunction usually resolves in about 2 to 5 weeks, an element of stunned myocardium
has been implicated.28, 29 However, as Takotsubo cardiomyopathy is usually associated
with elevations of cardiac enzymes, it is likely that once the acute episode is resolved,
there is a mix of irreversibly injured cells (that die) as well as reversibly injured
cells that survive. The cause of the apical ballooning is likely ischemia, but the
exact mechanism is still debated. Coronary angiography usually does not show classic
atherosclerotic narrowing. The arteries are often patent, suggesting elements of coronary
artery vasospasm, perhaps microvascular spasm, or plaque rupture with spontaneous
thrombolysis. Adrenergic hyperactivity or a sympathetic storm following stress may
play a role and contribute to coronary artery spasm, damage cardiomyocytes by calcium
overload, cause disorders of myocardial fatty acid metabolism, and contribute to atherosclerotic
plaque rupture with subsequent spontaneous thrombolysis.30 Postmenopausal low estrogen
levels have also been implicated. That Takotsubo cardiomyopathy is often associated
with emotional stress is exemplified by recent reports linking it to the emotional
stress associated with earthquakes.31 In experimental models, the administration of
high doses of isoproterenol (to mimic adrenergic hyperactivity/sympathetic storm)
has been used to study Takotsubo cardiomyopathy. In one study, our group observed
that rats exposed to isoproterenol exhibited LV apical akinesis, with preservation
of contractile motion in the basal portion of the left ventricle. Histologic and ultrastructural
analysis at 24 hours exhibited a mix of necrotic cells plus reversibly injured myocytes
showing vacuolization, lipid droplets, damaged mitochondria, and edema. Mononuclear
cell infiltration was also observed. On day 8 after exposure, the apical akinesis
fully resolved by echocardiographic analysis. Histologic analysis at day 8 revealed
foci of both necrosis and fibrosis plus areas of viable tissue in the apical regions.32
Thus, the fact that viable tissue in the apex is present at 8 days and the function
of the apex largely recovered after the initial insult on day 1 supports the concept
that stunned myocardium plays a major role in Takotsubo cardiomyopathy.
Table 2
Takotsubo (Stress) Cardiomyopathy
Stunned myocardium has been implicated
Often affects postmenopausal women
Chest pain and dyspnea
Often preceded by emotional stress
Signs of ischemia on ECG and elevated cardiac enzymes
Apical ballooning of the ventricle; significant organic stenosis often excluded on
angiography. Microvascular spasm or thrombus followed by spontaneous thrombolysis
may be involved. Territory of the apical ballooning often cannot be explained by obstruction
of just 1 coronary artery.
The left ventricular dysfunction usually resolves in 2 to 5 weeks, suggestive of stunning
Thought to be related to adrenergic hyperactivity
Absence of cerebrovascular events, pheochromocytoma, myocarditis, hypertrophic cardiomyopathy
Neurogenic Stunned Myocardium
Another relatively recently recognized phenomenon is “neurogenic stunned myocardium.”
While the term stunned myocardium is used to describe this phenomenon, whether it
really represents true stunned myocardium as originally described and occurs following
relief of a discrete episode of myocardial ischemia remains to be determined. Neurogenic
events such as stroke, subarachnoid hemorrhages, or seizures cause a sympathetic storm
that has also been associated with LV dysfunction. Some investigators categorize Takotsubo
stress cardiomyopathy as a type of “neurogenic stunned myocardium.”33 The clinical
findings may present similarly to acute MI with ischemic ECG changes (transient ST‐segment
elevations and T‐wave inversions,34 QTc prolongation),35 LV wall motion abnormalities,
decreased overall cardiac function, and elevated cardiac troponin levels. Angiography
typically shows no mechanical obstruction of the coronary arteries and coronary vasospasm
may contribute. The phenomenon is thought to be related to a surge in catecholamines
after areas of the brain related to the autonomic nervous system have been damaged.36
The entity of neurogenic stunned myocardium does appear similar to Takotsubo cardiomyopathy
but shows more global hypokinesis rather than the regional wall motion abnormality
of apical ballooning. Improvement in function is observed within 2 to 5 days after
the neurologic event, again suggesting that stunned myocardium was a prominent feature
of this entity. Biso et al36 postulated that free radical release and calcium entry
into the cells with contraction band formation, cardiac enzyme release, and myocytolysis
play a role in the pathophysiology of neurogenic stunned myocardium.
Stunned Myocardium Associated With Dialysis
LV dysfunction has now been described during and after hemodialysis, and this has
been attributed by some investigators to stunned myocardium. Mahmoud et al37 examined
serial echocardiograms of 11 patients undergoing hemodialysis. All patients developed
≥2 new regional wall motion abnormalities during dialysis; these contractile abnormalities
persisted for at least 30 minutes after dialysis. Global longitudinal strain, a measure
of global LV contractility, was also impaired during and after dialysis.37 Penny et al38
showed that exercise preconditioning during dialysis could reduce the extent of stunning
associated with dialysis, determined by echocardiography.
Biomarker Release Associated With Stunned Myocardium
There is ongoing controversy regarding the meaning of biomarker release of creatine
kinase–myocardial band and cardiac troponin I and T associated with stunned myocardium.
Release of these markers, typically associated with MI, into the blood stream have
been well documented in experimental models of brief ischemia and reperfusion, not
usually associated with MI.39, 40 Cardiac troponin has also been detected in the circulation
after exercise or pacing‐induced ischemia,41 as well as after vigorous bouts of exercise
not necessarily associated with known ischemia. It is unknown whether this biomarker
is leaking from many cardiac cells that are reversibly injured or a few cells that
are irreversibly injured. A recent investigation by Weil et al42 used a pig model
of myocardial stunning, induced by a 10‐minute coronary artery occlusion and reperfusion.
They observed a pathologic elevation of cardiac troponin I by 60 minutes after reperfusion
and continued elevation at 24 hours. Although tissue staining with triphenyltetrazolium
chloride and histologic analysis did not demonstrate classic ischemic necrosis, sections
obtained 1 hour after reperfusion showed a 6‐fold increase in terminal deoxynucleotidyl
transferase dUTP nick end labeling–positive cardiomyocytes in the region of ischemia/reperfusion.
Therefore, their study suggests that the elevation of troponin I after a period of
stunning is not associated with classic ischemic necrosis but with some cells that
undergo apoptosis (programmed cell death). The clinical significance of this finding
remains to be determined.42
Diagnosing Stunned Myocardium
How is stunned myocardium diagnosed? In some cases, the diagnosis will be retrospective
with the observation that, after an episode of ischemia is relieved, there is a gradual
improvement in LV function over time. In some cases, the diagnosis can be made prospectively
by finding evidence of a “flow‐function mismatch,” which usually would be discovered
by various imaging techniques. For example, the finding of a contractile dysfunction
(by ventriculography, echocardiography, nuclear, or other imaging technique) after
relief of a discrete episode of ischemia in the same area as normal perfusion (by
thallium scintigraphy, positron emission tomography [PET], echocardiography contrast)
is suggestive of stunning, especially if the region is shown to be viable (normal/enhanced
glucose metabolism by PET; Figure 2). Nuclear imaging techniques have documented the
presence of stunned myocardium following episodes of unstable angina.43 Recent studies
suggest that adding a measure of wall thickening in addition to EF measure on single‐photon
emission computed tomography imaging, improved the ability to diagnose stunned myocardium.44,
45 Viability is also suggested if the region that demonstrates contractile dysfunction
shows improved function with inotropic stimulation.
Hibernating Myocardium
Background
The concept of hibernating myocardium (Figure 2, Table 3) was first proposed by Dr
George Diamond in 197846 and then popularized by Dr Shahbudin Rahimtoola in 1989.47
The initial concept was that a region of the myocardium was supplied by an atherosclerotic
coronary artery in which enough blood supply was present to maintain viability but
not enough to maintain normal contractility of the region. In the setting of low blood
flow (reduced oxygen supply), there was an adaptive downregulation of function (reduced
oxygen demand) and metabolism to minimize ischemia and prevent myocardial necrosis.48
Rahimtoola's description of a typical case of hibernating myocardium reported the
LV angiographic results of a patient who preoperatively had a single vessel occlusion
(left anterior artery descending) with an EF of 37% and pronounced anteroapical akinesis
of the left ventricle. However, after nitroglycerin, the EF improved to 51% and there
was improved regional wall motion of the anteroapical region of the left ventricle,
demonstrating active contraction (and viability) in regions that were not moving before
nitroglycerin. Eight months after coronary artery bypass surgery to the left anterior
descending artery, the EF was 76% and the anteroapical region of the left ventricle
exhibited normal wall motion. Thus, a region of the myocardium that initially appeared
akinetic, but was shown to be viable after nitroglycerin challenge and was therefore
“hibernating,” had eventually recovered full function after revascularization.49 The
regional wall motion abnormality caused by hibernating was present chronically, was
related to low blood flow, without MI, and demonstrated the potential to recover (wake
up out of hibernation) once blood flow was restored. The downregulation of function
and metabolism would counter the reduced perfusion and could even prevent ischemia,
and certainly prevent painful ischemia. In contrast to stunning, which is a result
of a discrete episode of ischemia (lasting minutes to hours), followed by impaired
ventricular performance that might persist for hours to days, hibernating myocardium
results from months to years of reduced perfusion. The contractile dysfunction lasts
until blood flow is re‐established and then slowly recovers.50
Figure 2
Schematic representation of imaging findings in stunned and hibernating myocardium.
Top panel: The heart is shown as a conical structure with the base at the top and
the apex at the bottom with the ventricular cavity in the middle. Stunned myocardium
occurs after relief of a discreet episode of ischemia. During ischemia, imaging studies
(such as nuclear studies using thallium or other tracers, echocardiographic contrast
agents, magnetic resonance contrast imaging) will show reduced perfusion. During active
ischemia, reduced perfusion of the apex is associated with reduced cardiac function
(contractility) in the same apical region. Cardiac function can be measured by a variety
of techniques, including real‐time nuclear imaging, echocardiography, and magnetic
resonance imaging. After restoration of flow (angioplasty, stenting, thrombolysis,
relief of coronary vasospasm), perfusion is restored but there is a persistent region
of reduced cardiac function. The functional abnormality may last hours to days to
weeks but eventually does recover. The myocardium shows positive viability (usually
performed with positron emission tomography such as fluorodeoxyglucose uptake showing
active metabolism and therefore viable metabolizing cells). Bottom panel: Hibernating
myocardium is shown. At the apex there is eventually an area of reduced perfusion.
In the early phase, this area may be characterized by normal resting flow with reduced
coronary reactivity. Repetitive stunned myocardium may contribute as described in
the text. The chronically (months to years) reduced perfusion is matched by a chronic
reduction in cardiac function at the apex. The myocardium is viable as shown by studies
such as positron emission tomography.
Table 3
Clinical Evidence of Hibernating Myocardium
Chronic left ventricular wall motion abnormalities coupled with evidence of viability
(usually involves imaging techniques such as positron emission tomography, magnetic
resonance imaging, nuclear) and reduced perfusion
Eventual recovery of chronic left ventricular wall motion abnormality after revascularization
Biopsy evidence of dedifferentiated cardiomyocytes in an area with reduced wall motion,
reduced perfusion.
Area of myocardium that is akinetic or dyskinetic and presumed dead that then contracts
after inotrope, nitroglycerin (suggests both viability and potential to contract)
What is New and Controversial?
In the article by Braunwald and Kloner describing stunned myocardium, the authors
postulated that the myocardium could become chronically stunned as a consequence of
repetitive episodes of myocardial ischemia. In retrospect, this description may have
actually described the situation of hibernating myocardium.1 There has been controversy
regarding the issue of whether hibernating myocardium is the result of chronically
reduced resting coronary flow or whether hibernation is caused by repeated episodes
of ischemia/stunning48 as observed in a validated swine model.51 This latter concept
would suggest that repetitive episodes of stunning1 lead to hibernating myocardium.52
With this theory of hibernating, the key problem is one of inadequate coronary flow
reserve, such that resting flow is normal, but the coronaries cannot accommodate an
increase in oxygen demand, resulting in repeated episodes of supply‐demand imbalance,
with development of reduced ventricular function and adaptation of metabolism to reduce
active ischemia. Using a chronic ameroid constrictor model in pigs, Canty and Fallavollita53,
54 showed that repetitive episodes of stunning over time also resulted in a downregulation
of myocardial blood flow that reduced the mismatch between function and flow. They
showed that there is a continuum from stunning that originally is associated with
normal return of flow to repetitive stunning and then hibernating with reduced resting
flow, thus reconciling the 2 theories regarding flow in hibernating myocardium. Clinical
studies have also suggested varying degrees of flow‐function mismatch in patients
with wall motion abnormalities.55 That altered coronary flow reserve is a key component
of hibernating myocardium in patients and animal models has now been described in
several studies.56, 57, 58, 59, 60
Phenotype of the Hibernating Myocyte
Whichever the exact mechanism, there is evidence that the myocardium can adapt to
a low flow state. Experimental studies by Fedele et al61 showed that a partial stenosis
in an animal model resulted in metabolic adaptation by the heart to minimize or reverse
metabolic characteristics of ischemia. In the early minutes of placing a stenosis
on the coronary artery, myocardial lactate consumption had turned to lactate production,
but by 20 minutes to 1 hour after placing the stenosis, the degree of lactate production
had fallen and by 2 hours after stenosis, metabolism had reverted to lactate consumption.61
In addition, at 5 minutes after coronary stenosis, regional venous pH had fallen to
acidic levels, but by 1 to 3 hours after stenosis, pH returned to baseline. Histopathologic
and electron microscopy of areas thought to be hibernating were assessed after obtaining
biopsies during coronary artery bypass surgery.62, 63 These hibernating myocardial
cells typically show a loss of contractile filaments with sarcomeres often confined
to the periphery of the cells. Large spaces toward the center of cells show excess
glycogen granules in the cytosol, small mitochondria, and loss of sarcoplasmic reticulum
and transverse tubules. The cells also stain positively for excess glycogen on periodic
acid–Schiff staining. The myocardial cells appear “dedifferentiated” in that they
appear to have switched to a fetal phenotype. A possible analogy is what happens if
you break your arm and your arm is placed into a cast. The muscles are not being used
and therefore atrophy. In hibernating myocardium, the heart muscle cells are also
not contracting, so a degree of atrophy or even dedifferentiation is not unexpected.
Revascularization would therefore not expect to return function to normal immediately;
rather, there would need to be time for the muscle cells to replenish their sarcomeres
and regrow. Indeed, in an experimental study, a chronic stenosis of the left anterior
descending artery was created in swine to produce hibernating myocardium. By 3 months
there was depressed wall thickening in the left anterior descending region without
infarction. While revascularization normalized blood flow, there was no immediate
improvement in wall thickening of the left anterior descending region. Rather, wall
thickening gradually improved but remained depressed at 1 month after revascularization.
Following revascularization myocardial cells re‐entered the growth phase of the cell
cycle and increased myocyte nuclear density, with new formation of protein.64
A study by Lionetti et al65 examined the histological and molecular features of hearts
from patients undergoing transplantation for ischemic cardiomyopathy compared with
hearts of patients with dilated cardiomyopathy. Histologic and molecular features
associated with hibernating myocardium were observed in both hearts of patients with
ischemic cardiomyopathy and hearts of patients with dilated cardiomyopathy (despite
patent coronary arteries and less fibrosis in the dilated cardiomyopathy cohort).65
These findings suggest that some of the pathophysiology associated with hibernating
myocardium may apply to dilated cardiomyopathy as well.
Imaging of Hibernating Myocardium
Various imaging techniques have been used to diagnose hibernating myocardium in patients.
A perfusion‐metabolism mismatch showing absent or reduced perfusion in a region that
is not contracting, but demonstrates active metabolism (such as fluorodeoxyglucose
uptake), suggests hibernation.66 Hibernating myocardium has also been diagnosed by
assessing contractile reserve, usually using echocardiography or magnetic resonance
imaging (MRI) and low‐dose dobutamine. A region of the myocardium not initially contracting
may contract when stimulated inotropically by low‐dose dobutamine. High‐dose dobutamine
may make contraction worse, presumably by inducing ischemia. The fact that a region
of the ventricle initially responds to the low‐dose inotrope proves that the region
is not dead and has contractile reserve. Ruling out MI or scar is also part of the
imaging workup of hibernating myocardium and can be achieved by MRI (ruling out late
gadolinium enhancement) or scarring by echo or identifying LV wall thickness >5 to
6 mm, which would be unlikely in a transmural infarction. Gunning et al67 compared
several techniques for predicting hibernation and assessed biopsies of the ventricle
for myocyte volume fraction. In this study, true hibernating myocardium was assessed
by determining improvement in postoperative function. Thallium was the most sensitive
imaging technique for predicting hibernating myocardium, whereas MRI was the most
specific. Myocyte volume fraction assessed upon biopsies was higher in those segments
predicted to be hibernating rather than scar and was higher when both thallium and
MRI predicted hibernation.
Viability Testing of Revascularization Therapy
How important is viability testing before going forward with a revascularization procedure?
The issue of viability testing remains controversial.48 A 2002 meta‐analysis by Allman
et al68 suggested that there was a close association between testing for viability
and improved survival following revascularization therapy versus medical therapy alone.
While, if there was an absence of viability, then there was no difference in survival
outcome between revascularization therapy versus medical therapy. In this analysis
of >3000 patients with CAD and LV dysfunction (EF 32%), viability testing was assessed
using thallium perfusion, fluorodeoxyglucose metabolic imaging, or dobutamine echocardiography.
In patients showing areas of viability, revascularization resulted in an annual mortality
rate of 3.2% over an average of 25 months compared with 16% with the medical treatment
alone (no revascularization) groups (P<0.0001). Thus, there was a 79.6% reduction
in annual mortality by revascularizing areas of viability compared with no revascularization.
In patients without viability, there was no difference in annual mortality between
revascularizing (7.7%) or medical therapy (6.2%). This analysis would therefore favor
the use of viability testing. A recent subanalysis of the PARR‐2 (PET and Recovery
Following Revascularization‐2) study analyzed 182 patients with LV dysfunction and
CAD who underwent assessment for PET mismatch between perfusion and active metabolism.
Patients with larger amounts of mismatch (and therefore larger amounts of hibernating
myocardium) had better clinical outcomes (less cardiac death, MI, or cardiac hospitalization)
with revascularization therapy.69 However, the STICH (Surgical Treatment for Ischemic
Heart Failure) trial called into question the importance of viability testing. Among
1212 patients enrolled in the trial who had severe CAD and an LVEF <35%, 610 had viability
testing (single‐photon emission computed tomography and/or dobutamine echocardiography)
and were randomized to medical therapy plus coronary artery bypass grafting (CABG)
or medical therapy alone. There was no significant interaction between viability status
and treatment with respect to mortality. The assessment of viability did not identify
patients with a different survival benefit from CABG.70 Of note, at 5 years, there
was no significant reduction in mortality with CABG versus medical therapy.71 There
was a modest 8% reduction in mortality with revascularization compared with medical
therapy alone reported at 10 years of follow‐up.72 Did this trial spell the end to
viability testing for the issue of revascularization? There were a number of criticisms
regarding the viability issue in the STICH trial including the following: tests such
as MRI or PET may have been more accurate for viability than single‐photon emission
computed tomography or dobutamine echocardiography performed in the STICH trial, with
only less than half of the total patients enrolled in STICH having viability testing;
40% of the patients enrolled were asymptomatic; patients were not assessed for ischemia;
postoperative LV volumes were not reported; and other weaknesses continue to be debated.73,
74, 75, 76, 77, 78 A follow‐up article by the STICH group monitored patients out to
>10 years and again concluded that myocardial viability testing did not help delineate
the benefits of revascularization with CABG versus medical therapy in patients with
ischemic cardiomyopathy.79 However, this study did show that increases in LVEF were
only observed in those patients who had evidence for viability, irrespective of whether
the patients received CABG plus medical therapy or medical therapy alone, suggesting
that at least the diagnosis of viability was associated with eventual recovery of
some degree of function. Another fairly recent study failed to show an overall benefit
of PET imaging for management of patients with CAD and LV dysfunction, although some
subpopulations may benefit.80 Arora et al81 also observed mixed results when assessing
usefulness of PET imaging to predict recovery of LV perfusion and EF following CABG.
However, a more recent study showed that viability testing using MRI (low‐dose dobutamine
for contractile reserve and late gadolinium enhancement for visualization of scar)
could predict improvement in long‐term functional recovery of the left ventricle,
although this improvement in function was considerably delayed and required up to
35 months. In this study, the presence of contractile reserve best predicted earlier
ventricular functional improvement.82 Thus, debate continues about the usefulness
of viability testing as a management tool for whether to go forward with revascularization
procedures.
Another Approach to Treating Hibernating Myocardium
The therapy of choice for the treatment of hibernating myocardium is revascularization,
which can take the form of PCI (angioplasty and/or stenting) or coronary artery bypass
surgery. However, as mentioned, revascularization may not lead to immediate recovery
of function, and delay in return of function should be expected as myocardial muscle
cells may go through a phase of stunning and may take considerable time to rebuild
their contractile machinery. Another approach has recently been described in the experimental
literature. This concept involves injecting stem cells (mesenchymal stem cells and
mononuclear cells) into models of myocardial ischemia, which in several studies improved
cardiac function and improved coronary perfusion.83 Weil,84 Canty,53,54 and others
assessed the efficacy of intracoronary‐delivered allogeneic mesenchymal stem cells
and cardiosphere‐derived cells using a swine model of hibernating myocardium. Pigs
were subjected to a chronic left anterior descending coronary artery stenosis. Three
months after instrumentation, when the percent wall thickening of the anterior wall
was reduced (38% versus 83% in control nonischemic tissue), treatment with one of
the stem cell types was initiated and compared with vehicle. The pigs were immunosuppressed
with cyclosporine to avoid a rejection phenomenon. Four weeks after cell therapy,
the percent wall thickening of the anterior LV wall remained depressed (34%) in the
vehicle group, whereas it recovered to 51% in both the allogeneic mesenchymal stem
cell group and also to 51% in the cardiosphere‐derived cell group. Both therapies
improved myocyte nuclear density and reduced cell hypertrophy in both the ischemic
and remote regions of the left ventricle. The stem cell therapies did not increase
tissue perfusion in this study. The authors concluded that both stem cell types had
similar therapeutic efficacy in improving regional function of hibernating myocardium
in this large animal model.84 Thus, another approach to the treatment of hibernating
myocardium, besides simply revascularizing the myocardium, is to consider regenerative
techniques such as some types of stem cell therapy.
Summary
The phenomena of stunned myocardium and hibernating myocardium were first described
decades ago but they remain clinically relevant problems. Stunned myocardium remains
an issue following contemporary reperfusion therapy for acute MI and can contribute
to post‐MI LV dysfunction and heart failure. Exercise‐induced stunning is now well
recognized. Recently, 3 conditions have been described that may also involve an element
of stunning: stress cardiomyopathy (Takotsubo), “neurogenic stunned myocardium,” and
LV abnormalities associated with dialysis. One clinical study showed that the heart
rate–slowing drug, ivabradine, was effective in reducing exercise‐induced stunning.
Hibernating myocardium is still a condition that can contribute to heart failure and
ischemic cardiomyopathy. Hibernating myocardium may begin as repetitive episodes of
stunning with normal resting coronary blood flow between episodes but eventually result
in a chronic wall motion abnormality with reduced resting blood flow. There is a characteristic
phenotype of the hibernating cardiomyocyte that includes sparse contractile elements
located at the periphery of cells with central cytoplasm containing abundant glycogen
granules and small mitochondria. Hibernating myocardium can be diagnosed by a variety
of imaging techniques. While revascularization of hibernating myocardium improves
cardiac function, there is still controversy regarding the importance of viability
testing. Experimental studies suggest that a novel therapy for hibernating myocardium
involves stem cell therapy.
Disclosures
None.